1. Technical Field
The present invention refers in general to the technical field of organic synthesis of compounds with characteristics of electro-bistability, for use in the electronics industry to produce non-volatile memory devices.
In particular, the invention concerns a process for solid phase synthesis of halogenated derivatives of fluorescein, and their use as electro-bistable materials in non-volatile memory devices.
2. Description of the Related Art
Fluorescein and its derivatives are organic, aromatic, heterocyclic molecules derived from xanthene and are characterized by a general molecular structure according to the following formulae (I) and (II):
in which formula (I) corresponds to a lactone form of fluorescein and formula (II) corresponds to that of its derivatives, which have one or more various residues or functional groups R in different positions of the aromatic rings (i.e., each n is independently 0, 1, 2, 3 or 4).
The class of fluoresceins comprises highly fluorescent molecules that are used in numerous fields of application, from medicine to microelectronics. From the point of view of safety and environmental compatibility, these materials are not dangerous; indeed, they are biodegradable and non-toxic to man, and, if swallowed or injected into the human body, they are eliminated through the kidneys within 24 hours. See, e.g., http://www.sigmaaldrich.com/catalog/serch/ProductDetail/SIAL/F6377
In medicine, for example, fluorescein and frequently fluorescein-isothiocyanate or FITC, are widely used in immunofluorescence techniques. FITC, for example, is used to label different biomolecules, like for example, immunoglobulins, lectin, different proteins, peptides, nucleic acids, polynucleotides, oligo and polysaccharides. The products thus labeled are used as reactants for dyeing biomolecular sections by affinity, for immunodyeing and for dyeing by in situ hybridization, but also for the dyeing of living cells and for dyeing in flow cytometric methods, as they are not toxic for the host organism. Fluorescein is used, for example, in opthalmology as contrast dye for fluoroangiographic examinations, which study the anatomical alterations of the retina through the intravenous introduction of the dye followed by a photographic sequence of the eye fundus (retina). Moreover, thanks to its characteristically intense fluorescence, even in extremely diluted conditions, the molecule is normally used in the field of hydrogeology as hydrological tracer in the analysis of water tracing in underground basins. See, e.g., Bandiera, F. Sardegna Speleologica, 16, (1999).
In the field of microelectronics, on the other hand, it is known from literature that fluorescein and some of its derivatives are promising materials for organic-based non-volatile memory devices.
The increasing miniaturization of the electronic devices has recently also hit the field of non-volatile memories. However, if on the one hand this trend corresponds to a substantial increase in the integration density on a chip, in parallel it requires substantial economic engagement aimed at overcoming a series of technological limitations. The use of organic materials as memory elements and the adoption of process technologies, alternative to those currently in use for semiconductor (e.g., silicon) devices, are greatly motivated by the possibility of overcoming the aforementioned technological limitations and pushing the comminution up to molecular level.
It is known from literature that some organic molecules can have logic functions and memory functions, due to switch phenomena between stable states. In particular, the physical property of an organic material that is most suitable for use as memory element is electro-bistability. From the physical point of view, an electro-bistable material is defined as a material that shows a variation in electrical conductivity passing from a highly resistive state to a conductive state under the effect of an electrical field, as shown in FIG. 1.
In terms of architecture, the innovative memory devices, having organic materials as memory elements, are made according to a “pad size” structure, resulting from the repetition of “cross-point” memory cells. The organic memory element, in the form of a thin film, is placed between two electrodes, made of metal and/or conductive oxides, according to the schemes of FIG. 2 and of FIG. 3.
This type of device can be made by using fairly well established low-cost process technologies, both in terms of the deposition of the electrodes and of the memory element. In particular, the pattern of bottom electrodes can be made by using physical vapor deposition (PVD, sputtering) technologies and the deposition of the memory element, in the form of a thin film can be carried out through low-temperature vapor phase (PVD) processes or more frequently through spin-coating and therefore through a liquid phase deposition technology. Indeed, it is known that organic materials can be effectively manipulated from liquid phase thanks to their high solubility in low-boiling point organic solvents (chlorinated hydrocarbons, alcohol hydrocarbons, ethers, esters, etc). The deposition, which is the last step of the assembly process of the device, can analogously be carried out through physical vapor deposition (PVD, sputtering) technologies.
For an electro-bistable organic material to be used as memory element, the transition between the resistive and conductive states should suitably take place in standard conditions of temperature and pressure, the potential range should be fairly narrow (about 10 V), the ratio between the resistivities of the two states (ON/OFF) should suitably be at least by a factor of 103, the transition should take place in short times (<100 ns) and finally the number of writing/reading/cancellation cycles should be at least 104. In literature, different materials are disclosed that display such a property. The physical mechanisms responsible for electro-bistability can include structural rearrangements, through changes in configuration, modifications of the conjugation of the mobile π-electrons, via electroreduction, or both factors.
Fluorescein, and in particular, some haloderivatives of Fluorescein, as shown in the following formulae, display properties of electro-bistability with electrical performance, relative to non-volatile memory devices, that improves according to the number of electron-withdrawing substituents (e.g., halogens) on the skeleton of the molecule. See, e.g., Bandyopadhyay, A. et al, Applied Physics Letters, 82,1215, (2003); Bandhopadhyay, A. et al, J. Phys. Chem. B, 107, 2531, (2003); Majee, S. K. et al, Chem. Phys. Lett, 399, 284, (2004); Bandyopadhyay, A. et al, J. Phys. Chem. B, 109, 6084, (2005).

Prototypes of memory cells based on fluorescein and its derivatives have exhibited interesting electrical characteristics: by applying an increasing potential difference in the range 0-4 V, an extremely low current is recorded due to the high resistivity of the molecules (OFF state). In particular, for a device having a thin film of Rose Bengal as the memory element, when the potential is above about 4 V, a clear increase in current is recorded due to a decrease in resistivity (ON state) that lasts until a negative voltage corresponding to −4V is applied, indicating that the material goes back to OFF state due to high resistivity, and the datum is “cancelled” (FIG. 4).
Analogous results have been obtained on devices having thin films of fluorescein and of Eosin Y as memory elements. The performance of the three devices, having fluorescein, Eosin Y and Rose Bengal, respectively, as memory elements, is shown in Table 1. See, supra. The table highlights an increasing trend of the ON/OFF ratio of fluorescein to Rose Bengal and this phenomenon is in relation to the number of electron-withdrawing substituent groups on the skeleton of the molecule. The presence of the electron-withdrawing groups in the two halogen-derivatives of fluorescein (Eosin Y and Rose Bengal) draws electrons, which has the consequence of perturbing the aromatic conjugation and therefore decreasing the conductivity of the OFF state. Such an effect leads to an increase in the ON/OFF ratio, proportionally to the number and nature of the electron-withdrawing groups present.
TABLE 1MoleculeStructureON/OFFCyclesFluorescein4>106 Eosin Y 2′,4′,5′,7′- tetrabromofluorscein9800>106 Rose Bengal 3,4,5,6-tetrachloro- 2′,4′,5′,7′-tetraiodo- fluorescein105>106
Although in the current state of the art there is no interpretative model of the phenomenon of bistability on a molecular basis, it is possible, in light of the data from literature, to identify in some functional groups and in certain structural features some important elements for achieving bistability. In particular, aromatic rings carrying electron-rich and/or electron-withdrawing substituents and the presence of hindered diphenyl systems constitute a recurrent theme in molecules exhibiting bistability. Moreover, the organization of bistable molecules into regular domains within films influences the electrochemical parameters of the devices made, in particular, films having highly regular domains display better ON/OFF range values and relative resistance ratio values between the resistive state and conductive state.
The halogenations of aromatic organic molecules are electrophilic substitution reactions, which are conducted, conventionally, in liquid phase and based upon the use of hydrohalogenic acids or of molecular halogens as halogenating agents. See, e.g., http://v3.espacenet.com/results?AB=halogenation+of+phenols&sf=q&FIRST=1&C Y=gb&LG=en&DB=EPODOC&st=AB&kw=halogenation+of +phenols&=&=&=&=&=Tetrahedron 55 (36), pp. 11127-11142 (1999); J. Am. Chem. Soc. 84,1661 (1962); J. Am. Chem. Soc. 81,1063 (1959); J. Am. Chem. Soc. 82, 4547 (1960); and J. Am. Chem. Soc. 79, 5169 (1957). The halogenation rates and the reactivity of halogens towards organic substrates depend upon numerous factors: mainly the halogen and the number, type and position of the substituent groups in the organic substrate. Generally, molecular chlorine and bromine are highly reactive towards aryl substrates. “Aryl substrate” refers to an aromatic molecule having delocalized π-electrons. Typically, Lewis acids are used to increase the rate of the reactions. Molecular fluorine reacts very violently and the reaction conditions always have to be carefully controlled, and finally molecular iodine only reacts with very reactive aromatic substrates.
The role of Lewis acids of the HA type is to promote the aromatic electrophilic substitution process by assisting in breaking the X—X link of the halogen molecule (X2), as shown in the following chlorination scheme:

The catalytic mechanism of Lewis acids of general formula MXn, is analogous to that of HA acids. For chlorination reactions, metal salts such as ZnCl2 and FeCl3 or elementary metals, are generally used as Lewis acids, and molecular chlorine is generally used as the chlorinating agent, as shown in the following scheme:

Other factors that impact the halogenation process in liquid phase include the proticity and polarity of the solvent. For example, chlorinations are much faster in polar solvents than in non-polar solvents. See, e.g., J. Am. Chem. Soc. 83, 4605 (1961).
Similarly to what has been described for the chlorination process, numerous aromatic substrates can be brominated. For example, phenyl derivatives and aniline derivatives in particular are reactive to bromination. The use of Lewis acids, as catalysts, also promotes the bromination of deactivated aromatic substrates, i.e., those functionalized with electron-withdrawing substituents, like nitro-groups and cyano-groups. See, e.g., J. Org. Chem. 53, 1799 (1988).
Another known synthetic scheme discloses the use of mercury acetate or mercury trifluoroacetate as catalysts. The synthetic strategy on which it is based involves the formation of acetyl or trifluoroacetyl hypohalogenites as the halogenating species and generally it is adopted for the halogenation of very deactivated aryl substrates. See, e.g., J. Am. Chem. Soc. 94, 6129 (1972). The formation of acetyl or trifluoroacetyl hypohalogenites is regulated by the equilibrium displayed in the following scheme:

As far as the iodination reactions are concerned, in addition to the use of molecular iodine in the presence of Lewis acids, there are alternative synthetic schemes using mixtures of metal iodide and cerium ammonium nitrate [Ce(NH3)2(NO3)6] as iodinating agents, or mixtures of molecular iodine and silver and mercury salts.
Recently, a halogenation procedure of aromatic substrates, in particular arenes, in solid phase has been developed that uses metal halides as halogenating agents and diacetoxyiodobenzene as oxidizing agent. However, at this point in time there is no example of halogenation in solid phase of xanthene derivatives. See, e.g., J. Chem. Res., 6, 366 (2006). The halogenation processes that have been used up to now to synthesize halogen derivatives of fluorescein are invariably carried out in a liquid phase with the help of a solvent, which imposes numerous process stages, such as extraction, dehydration, filtering processes, etc., which in addition to being time-consuming and costly, can cause product losses. Moreover, such syntheses in liquid phase often require protection of functional groups and subsequent deprotection of them, which can substantially lower the reaction yields. See, e.g., J. Org. Chem., 68, 8264 (2003), and In. Chem., 43(26), 8310 (2004).